On one hand, “obesity-associated depression” is likely determined by two types of pathogenic determinants: a biologic determinant, consisting of perturbations in the psycho-immune-neuro-endocrine network (PINE network), such as chronic subinflammatory states, imbalance in the leptin-ghrelin system and leptin-ghrelin hypo-sensitivity, insulin resistance, gut dyspermeability, dysbiosis, endocrine and autonomic dysfunctions; and a psychological determinant, related to body image dissatisfaction, low self-esteem and consequent distress [10]. This evidence concerns the gene LEP and Obesity.